BOTH ESTRADIOL AND TAMOXIFEN DECREASE PROLIFERATION AND INVASIVENESS OF CANCER-CELLS TRANSFECTED WITH A MUTATED ESTROGEN-RECEPTOR

Previous studies have shown that, after wild-type estrogen receptor (E R) transfection in ER-negative breast cancer cells, estradiol but not tamoxifen prevents growth, invasiveness and metastasis of these cells in mice. Because an ER mutation at position 400 converts the triphenyl ethylene antiestrogen, OH-tamoxifen into a full estrogen agonist, we t ransfected this mutated form of human ER in an ER-negative rat cancer cell line. This was aimed at inducing an inhibitory, estrogen-like res ponse of tamoxifen in these cells. In two stable ER-positive transfect ants, OH-tamoxifen inhibited cell growth and invasiveness in vitro as efficiently as estradiol. The pure antiestrogen, ICI 164,384, was not agonistic alone and antagonized estrogen action. In contrast, the thre e compounds were ineffective in control mock-transfected cells. When i njected into ovariectomized nude mice, ER-negative mock-transfected ce lls formed tumours which were significantly stimulated by estradiol an d inhibited by tamoxifen treatment. This indicates that estradiol and tamoxifen altered the growth of ER-negative tumours via a general effe ct on the host response. Surprisingly, the hormone responsiveness of E R-positive tumours developed from ER-transfected cells did not signifi cantly differ from that of ER-negative (mock-transfected) tumours. We conclude that transfection of a mutated human estrogen receptor inhibi ted, through an estrogenic activity of tamoxifen, the growth and invas iveness of these cancer cells in vitro. However, the low expression of ER did not allowed us to obtain the same effect of tamoxifen in vivo. (C) 1997 Elsevier Science Ltd.